Ukrain: general information, physical, chemical and biological properties

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Since the first therapeutic use in 1978, Ukrain administered either as neoadjuvant treatment before surgery or as combination therapy or alone has been the subject of numerous experimental and clinical tests. Ukrain is reproducible and always produced as the same compound. It is confirmed chromatographically and in biological tests. Ukrain is a product that results from a reaction of alkaloids from greater celandine with Thio-TEPA in the presence of hydrochloric acid. These two main compounds, greater celandine alkaloids and Thio-TEPA, are approved and clinically widely used. Thio-TEPA is listed in many pharmacopoeia (e.g. UK, France, USA, Japan) and is approved as a cytostatic drug. Chelidonium majus (greater celandine) was first described in the so-called Ebers` papyrus in around 1550 BC and greater celandine extracts have been well known in herbal medicine for more than 3,000 years, in particular for the treatment of skin and gastrointestinal diseases. Chelidonium herba (Schöllkraut) is listed in the “Deutsches Arzneimittelbuch“ (DAB) 10, 2nd Appendix 1993. Greater celandine is used for the production of extracts which are ingredients of many drugs from the groups cholagoga and bile duct therapeutics, for example Aristochol®, Chelidophyt®, Cholagogum N Nattermann®, Cholarist®, Esberigal®, Gallopas® 100, Horvilan®, Panchelidon®, Zettagall® V etc. The active substance of the herbal remedies and extracts are alkaloids. DAB demands for the herbal remedy a minimum content of 0.6% alkaloids estimated as chelidonine (Fulde et al, 1994). Chelidonine is the main alkaloid of greater celandine. Chelidonine, like some other celandine alkaloids, is hardly soluble in water. This makes intravenous injections impossible. For this reason drugs derived from celandine alkaloids are always administered only orally. In addition, these drugs cannot accumulate in cancer tissue. Ukrain is a Chelidonium majus L.-thiophosphoric acid derivative, a complex reaction mixture of Chelidonium majus L. alkaloids with triethylene-thiophosphoric acid triamide (Thio- TEPA). The injection solution contains Ukrain in a concentration of 1 mg/ml. No Thio-TEPA or free aziridine ring compounds can be detected. The finished product contains still alkaloids, however, in contrast to the starting material, in a water-soluble, injectable, active form. The substance is patented: European Patent No. 0083600, US Patent No. 2,670,347. The active substance is a bright yellow crystalline hygroscopic powder which is readily water soluble. The injection solution is a transparent, bright yellow-brown liquid with the aroma of freshly cut grass and a bitter taste. The preparation comes as a sterile 0.1% (1 mg/ml) aqueous injection solution (pH: 3.5 to 6.5) in amber-coloured ampoules of 5 ml, with no excipients. Ukrain is readily soluble in water. Therefore it is possible to inject the drug intravenously without any excipients. It has a very strong affinity to cancer cells and accumulates in cancer cells. This has been proved by autofluorescence, radiography, and HPLC (Nowicky et al, 1988; Hohenwarter et al, 1992; Thakur et al, 1992). The National Cancer Institute (Bethesda, Maryland, USA) has proved that NSC 631570 (this abbreviation was given to Ukrain by the National Cancer Institute) has a completely different effect on malignant cells to Thio-TEPA (NSC 6396) and chelidonine hydrochloride (NSC 406034). For example: 7 • NSC 631570 is least effective [log(TGI) = -3.4] against leukaemia-HL-60(TB) in contrast to chelidonine hydrochloride, which is very effective [log(TGI) = -5.4] and to Thiotepa, which is only moderately effective [log(TGI) = -4.4]. • NSC 631570 is extremely effective [log(TGI) = -5.6] with Non-SmallLung-NCI-H460, chelidonine hydrochloride less effective [log(TGI) = -4.0] and Thiotepa shows very little effect [log(TGI) = -4.5]. • With Colon-SW-620, NSC 631570 is very effective [log(TGI) = -5.2], chelidonine hydrochloride is not effective [log(TGI) = -4.0], and Thiotepa is also not effective [log(TGI) = -4.2]. The profiles of these three different substances show very clearly that their effects on the same cell lines are very different. Results of the National Cancer Institute, Bethesda, USA, Human Cell Line Screen can be seen on the website of the Developmental Therapeutics Program NCI/NIH (National Cancer Institute, National Institute of Health) http://www.dtp.nci.nih.gov/. Until now NSC 631570 has been tested on more than 100 cancer cell lines and revealed malignotoxic action against all of them, including pancreas cancer cell lines, cis-platin resistant cell lines and human tumour xenografts. At the doses at which NSC 631570 kills cancer cells it does not affect healthy cell lines. The concentration of NSC 631570 which is toxic for healthy cells is more than 100 times higher than the concentration lethal for all cancer cell lines. Its therapeutic index is 1250 (Nowicky et al, 1996; Nowicky et al, 1996; Panzer et al. 1998; Roublevskaia et al, 2000; Cordes et al, 2002).